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Penthorum chinense Pursh has been widely used as a Chinese traditional functional food for liver disease prevention and therapy. A novel cold-water soluble polysaccharide (PCP-4) has been prepared from Penthorum chinense Pursh at 4 °C. PCP-4 contained both α and β configurations and mainly consisted of galactose, arabinose, galacturonic acid, rhamnose, and glucose (molar ratio: 6.38:5.26:1.69:1:0.87) with an average molecular weight of 1.83 × 106 Da. In vitro experiments results demonstrated that PCP-4 effectively inhibits the proliferation of H22 cells and blocks cells at S phase in a dose-dependent manner. Otherwise, PCP-4-treated cells exhibited typical morphological features of apoptotic cells. Combined the results from western blot analysis, Annexin V-FITC/PI staining, Rhodamine 123 staining and DCFH-DA staining, PCP-4 was found to induce H22 cell apoptosis in vitro via the mitochondrial signaling pathway. The results of in vivo experiments suggested that PCP-4 significantly suppresses xenograft tumor growth by protecting immune organs, enhancing immune cells functionality, and inducing apoptosis. Overall, these results clearly show that Penthorum chinense Pursh polysaccharide serves as a valuable natural product for hepatocellular carcinoma therapy. • A novel polysaccharide (PCP-4) was isolated from Penthorum chinense Pursh. • PCP-4 suppressed H22 cell proliferation and blocked cell at the S phase in vitro. • PCP-4 activated mitochondrial pathway to promote H22 cell apoptosis in vitro. • PCP-4 could significantly inhibit tumor growth in H22 tumor-bearing mice. • PCP-4 exerted inhibitory effect by enhancing immunity and inducing tumor apoptosis. [ABSTRACT FROM AUTHOR]

Our previous research revealed that carboxymethylation modification (CM-CP) and sulfation modification (S-CP) could enhance the antitumor activity of Cyclocarya paliurus polysaccharides (CP), however, the antitumor mechanisms of CM-CP and S -CP are not fully clarified and remain largely unexplored. The aims of the present study were to investigate the dual anti-tumor function of CM-CP and S -CP in inhibiting cancer cells and activating macrophages to exert immunomodulation. Results revealed that CM-CP and S -CP preferentially inhibited the proliferation of colon cancer CT-26 cells in dose-dependent and time-dependent ways, without toxicity to normal cell lines. Flow cytometry values further established that CM-CP and S -CP interventions elicited acidification in the cells, arrested the cell cycle in S stage, raised the amount of reactive oxygen species and activated oxidative stress. CM-CP and S -CP treatment elicited the depolarization of mitochondrial membranous potentials and Ca2+ superload, and disrupted the equilibrium of Na+/K+-ATPase and Ca2+-ATPase. Simultaneously, apoptotic proteins expression assays revealed that CM-CP and S -CP promoted CT-26 cell apoptosis through PI3K/AKT-MAPKs/NF-κB signal pathways. In parallel, CM-CP and S -CP dramatically promoted the proliferation and secretory activity (TNF-α and NO) of RAW264.7 cells. Co-culture of cancer cells with CM-CP and S -CP-stimulated macrophage supernatants resulted in more pronounced suppression of cancer cell viability. These findings demonstrated that CM-CP and CM-CP not only inhibit cancer cell growth directly, but also activate macrophages to exert immunomodulatory effects to suppress cancer cells. Furthermore, CM-CP and CM-CP make a contribution to the development of potential functional foods or supplements for the prevention or treatments of colorectal cancer. A tentative scheme for induction of apoptosis in CT-26 cancer cells by CM-CP and S -CP. [Display omitted] • Cyclocarya paliurus polysaccharide (CP) and its derivatives (CM-CP and S -CP) retarded CT-26 cells growth. • CM-CP and S -CP inhibited the growth of CT-26 cells via PI3K/AKT-MAPKs/NF-κB passway. • CM-CP and S -CP could exert antitumor effects on CT-26 cells via the activation of macrophages. • The antitumor activity of CP is affected by its type of substituent and the molar ratio. [ABSTRACT FROM AUTHOR]

It has been 11 years since ferroptosis, a new mode of programmed cell death, was first proposed. Natural products are an important source of drug discovery. In the past five years, natural product-derived ferroptosis regulators have been discovered in an endless stream. Herein, 178 natural products discovered so far to trigger or resist ferroptosis are classified into 6 structural classes based on skeleton type, and the mechanisms of action that have been reported are elaborated upon. If pharmacodynamic data are sufficient, the structure and bioactivity relationship is also presented. This review will provide medicinal chemists with some effective ferroptosis regulators, which will promote the research of natural product-based treatment of ferroptosis-related diseases in the future. [Display omitted] • 178 natural products that have been reported to resist or trigger ferroptosis are summarized. • Molecular mechanisms of ferroptosis regulators were described. • Natural products with ferroptosis inhibitory activity were categorized according to the mechanism of action. [ABSTRACT FROM AUTHOR]

The liver serves as the central organ for lipid metabolism, making it a crucial component of chicken physiology. However, the intricate regulation of lipid absorption, synthesis, decomposition, and transport within the liver is influenced by various factors, such as environmental conditions, diet, and genetics. Recent research has suggested that numerous functional genes and transcription factors play a pivotal role in liver metabolism via different molecular mechanisms. In this study, we examined the transcriptomes of both healthy and fatty chicken livers to better understand the role of functional genes in chicken liver fat metabolism. Our bioinformatics analysis of RNA-seq data revealed differential expression of SLCO1B3 in healthy liver and fatty liver, with lower ex-pression levels observed in fatty liver. To further investigate the potential role of SLCO1B3 in liver metabolism, we conducted in vitro experiments to knock down its expression in primary hepatocytes. Our results indicated that SLCO1B3 could suppress lipogenesis, hepatocyte apoptosis, and inflammation. These findings provide insight into the molecular mechanism of SLCO1B3 as a functional gene capable of regulating fat metabolism in chicken liver, and may contribute to ad-dressing the issue of fatty liver in chicken. [ABSTRACT FROM AUTHOR]

Background/purpose: Substantial progress was made in acute kidney injury (AKI) over the past 10 years, but no therapeutic interventions have been shown to prevent AKI or accelerate functional recovery after injury. A large number of preclinical studies supports the use of recombinant human erythropoietin (rHuEPO) to prevent AKI, but the clinical trial data are inconclusive. To address concerns about preclinical study design and reporting in AKI, we here presented our rigorous experiments on the use of rHuEPO in a mouse model simulating the most common post-ischemic AKI in patients.Methods: Use of saline vehicle or rHuEPO (100 or 1000 U/KgBW) in mice subjected to AKI induced by ischemia-reperfusion injury of left kidney 2 weeks after right nephrectomy (NX + IRI).Results: NX + IRI resulted in a reproducible AKI model. Use of rHuEPO as a pretreatment or posttreatment did not affect AKI severity, functional recovery, and mouse survival regardless of gender, injury severity, or doses of rHuEPO. Administering rHuEPO with 1000 U/KgBW did increase hematocrit and modulate AKI kidney macrophages by Nos2 downregulation and Ccl17 upregulation. Active expression of erythropoietin receptor (EPOR) was not identified in renal cells by lineage tracing study, whereas expression of colony-stimulating factor 2 receptor β (CSF2Rβ) was identified in kidney macrophages and upregulated after AKI. Both EPOR and CSF2Rβ were identified in cultured bone marrow derived macrophages, possibly mediated the robust inhibition of cytokine-induced phenotype switching by rHuEPO.Conclusion: Use of rHuEPO can modulate macrophage function but not the post-ischemic AKI severity, functional recovery and survival in mice. [ABSTRACT FROM AUTHOR]

Abstract Chronic stress can provoke depressive-like behaviors through activation of inflammation and apoptosis, leading to a reduction of neurons. Antidepressant therapy may contribute to inhibiting inflammation responses and have neuroprotective effects. Baicalin (BA) has an antidepressant effect in the chronic unpredictable mild stress (CUMS) animal model and exerts anti-inflammation, anti-apoptosis, as well as neuroprotective effects in many central nervous system (CNS)-related diseases. But the effects of BA on neuroprotection, apoptosis, and neuroinflammation and the potential mechanisms in depression are unclear. Here, we focused on examining the therapeutic effects of BA in CUMS-induced depression rats and investigating the molecular mechanisms. Results showed that administration of BA improved depressive-like behaviors and significantly increased the levels of doublecortin (DCX), Neuron-specific enolase (NSE), and Brain-derived neurotrophic factor (BDNF) in hippocampus. Furthermore, administration of BA increased the cell survival by reducing the level of malondialdehyde (MDA) and increasing the level of superoxide dismutase (SOD). Finally, administration of BA significantly decreased CUMS-induced apoptosis and inflammatory cytokines (caspase-1 and IL-1β) in hippocampus. These responses were mediated by Glycogen synthase kinase-3 (GSK3) β/Nuclear factor-κB (NF-κB)/Nucleotide-binding domain, leucine-rich repeat, pyrin domain containing protein 3 (NLRP3) signal pathway. Taken together, these results indicate that BA could promote neuronal maturation and rescue neurons from apoptosis via inhibiting activation of GSK3β/NF-κB/NLRP3 signal pathway that is known to be associated with inflammation, thus exerting neuroprotective effects and preventing CUMS-induced depressive-like behaviors. Highlights • CUMS procedure was used to establish a rat depression model. • Administration of BA improved the depressive-like behaviors. • Administration of BA protected hippocampal neurons. • Administration of BA decreased apoptosis and protected cells from oxidative stress. • BA ameliorated CUMS-induced neuroinflammation via inhibiting activation of GSK3β/NF-κB/NLRP3 signaling. [ABSTRACT FROM AUTHOR]

[Display omitted] • PA-B induced HSC-T6 cell apoptosis by inhibiting proliferation. • PA-B reduced mitochondrial membrane potential. • PA-B ameliorated apoptosis-related protein expression. • PA-B (120 mg/kg) significantly alleviated CCl 4 -induced hepatic fibrosis injury. • PA-B reduced the aspartate aminotransferase and alanine aminotransferase levels. Periplaneta americana L. (Blattidae) extract (PA-B) possesses anti-oxidant, anti-inflammatory, and hepatoprotective properties; however, its mechanism of action in liver fibrosis remains unclear. Herein, we investigated the hepatoprotective effect and mechanism of action of PA-B. HSC-T6 cells treated with PA-B were stimulated with TGF-β1, and immunofluorescence, western blotting, Hoechst 33,342 staining, confocal laser scanning microscopy, and flow cytometry were performed. Furthermore, the effects of PA-B were verified in a rat model of hepatic fibrosis established using 40 % carbon tetrachloride (CCl 4). PA-B induced apoptosis of HSC-T6 cells by inhibiting proliferation (maximum inhibition ratio 99.08 %), reducing mitochondrial membrane potential, and ameliorating apoptosis-related proteins (P < 0.01). PA-B (120 mg/kg) significantly alleviated CCl 4 -induced hepatic histopathological fibrosis and reduced the levels of aspartate aminotransferase (from 27.68 to 20.58 U/L) and alanine aminotransferase (from 16.88 to 5.93 U/L; P < 0.05 or P < 0.01). Immunohistochemistry and western blotting showed that α-SMA levels were reduced (from 0.49 to 0.23) and that the Bcl/Bax signaling pathway was significantly inhibited by PA-B (120 mg/kg; P < 0.05 or P < 0.01). PA-B exhibits anti-fibrotic effects by mediating the Bcl-2/Bax pathway and promoting HSC-T6 cell apoptosis, providing a basis for its development as a drug to treat liver fibrosis. [ABSTRACT FROM AUTHOR]

Background/purpose: Appropriate mechanical stress plays an important role in regulating the proliferation and differentiation of osteoblasts, whereas high-level mechanical stress may be harmful and compromise cell survival. Periostin, a matricellular protein, is essential in maintaining functional integrity of bone and collagen-rich connective tissue in response to mechanical stress. This study investigated whether or not high-level mechanical stretch induces cell apoptosis and the regulatory role of periostin in mechanical stretch-induced apoptosis in osteoblastic cells.Methods: Osteoblast-like MG-63 cells were seeded onto Bio-Flex I culture plates and subjected to cyclic mechanical stretching (15% elongation, 0.1 Hz) in a Flexercell tension plus system-5000. The same process was applied to cells pre-treated with exogenous human recombinant periostin before mechanical stretching. We used a chromatin condensation and membrane permeability dead cell apoptosis kit to evaluate the stretch-induced cell responses. Expression of caspase-3 and cPARP was examined by immunofluorescent stain and flow cytometry.Results: The expression of periostin in MG-63 cells is involved in the TGF-β signaling pathway. High-level cyclic mechanical stretch induced apoptotic responses in MG-63 osteoblastic cells. The percentages of apoptotic cells and cells expressing cPARP protein increased in the groups of cells subjected to mechanical stretch, but these responses were absent in the presence of exogenous periostin.Conclusion: Our study revealed that high-level mechanical stretch induces apoptotic cell death, and that periostin plays a protective role against mechanical stretch-induced apoptosis in osteoblastic cells. [ABSTRACT FROM AUTHOR]

Tea ( Camellia sinensis ) flower saponins (TFS) have various biological properties. However, the anti-cancer effects of TFS have not been investigated in any detail. Here, we evaluated the anti-cancer effects of TFS using human ovarian cancer cell lines. TFS (1.5 μg/ml) produced significant antiproliferative effects against A2780/CP70 and OVCAR-3 cells by inducing p53-dependent apoptosis and S phase arrest. Further study showed that TFS decreased mitochondrial membrane potential, activated Caspase-3/7, Caspase-8 and Caspase-9 activities, and that the p53 inhibitor PFT-α reversed the TFS-induced cell growth inhibition and apoptosis. In addition, TFS inhibited the expression of Cdc25A, Cdk2, and CyclinD1 and upregulated Cyclin E and Cyclin A, suggesting that the Cdc25A-Cdk2-Cyclin E/A pathway was involved in TFS-induced S phase arrest. Furthermore, the S phase arrest was associated with a Chk2-Cdc25A DNA damage response. These results demonstrated that TFS has promising potential serving as functional food components for prevention of ovarian cancer. [ABSTRACT FROM AUTHOR]

As an indispensable process of cell life, apoptosis is essential for keeping homeostasis at cell level. Dysregulation of apoptosis is usually involved in the pathological processes of many complex diseases including cancer. With the properties such as high affinity and specificity to their targets, easy of synthesis and modification and good biocompatibility, aptamers have been attractive molecules applied in basic research, diagnostics and therapeutics. This review mainly focuses on the recent researches on application of aptamers in interference of cell apoptosis. Key targets along the intrinsic and extrinsic apoptosis pathways were respectively dissected using aptamers as a tool, providing an insight into the pathological processes, especially for cancer. [ABSTRACT FROM AUTHOR]

The tautomeric pair of garcinielliptone FC (GFC) is a pure and structure-defined active ingredient, isolated from Garcinia subelliptica Merr., a plant with abundant sources of polyphenols. Here, we demonstrate that a higher concentration of GFC had no effect on normal human umbilical vein endothelial cells. On chemoresistant human colorectal cancer HT-29 cells, a time- and dosage-related cytotoxicity was observed. GFC also inhibited the nuclear expression and DNA binding activity of nuclear factor κB in a time- and dosage-related manner using Western blot and electrophoretic mobility shift assay. Furthermore, GFC induced apoptosis, which was characterized by an increase of cells at the sub-G1 phase, induction of DNA fragmentation, and formation of apoptotic bodies using flow cytometry, electrophoresis, and fluorescence microscopy, respectively. Western blot analysis revealed that both caspase-dependent intrinsic and extrinsic pathways as well as caspase-independent pathway were involved. Our data suggest the anticancer mechanisms of GFC on human colorectal cancer. [ABSTRACT FROM AUTHOR]

In our continued focus on 1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole (YC-1) analogs, we synthesized a novel series of 3,9-substituted α-carboline derivatives and evaluated the new compounds for antiproliferactive effects. Structure activity relationships revealed that a COOCH 3 or CH 2 OH group at position-3 and substituted benzyl group at position-9 of the α-carboline nucleus were crucial for maximal activity. The most active compound, 11 , showed high levels of cytotoxicity against HL-60, COLO 205, Hep 3B, and H460 cells with IC 50 values of 0.3, 0.49, 0.7, and 0.8 μM, respectively. The effect of compound 11 on the cell cycle distribution demonstrated G2/M arrest in COLO 205 cells. Furthermore, mechanistic studies indicated that compound 11 induced apoptosis by activating death receptor and mitochondria dependent apoptotic signaling pathways in COLO 205 cells. The new 3,9-substituted α-carboline derivatives exhibited excellent anti-proliferative activities, and compound 11 can be used as a promising pro-apoptotic agent for future development of new antitumor agents. [ABSTRACT FROM AUTHOR]

The cytotoxic activity of litchi ( Litchi chinensis Sonn.) flower ethanolic extract (LFEE) against A549 (human lung adenocarcinoma), KB (human nasopharyngeal carcinoma), MCF-7 (human breast adenocarcinoma) and HepG2 (human hepatocellular carcinoma) cells was evaluated. LFEE exhibited better anti-proliferative action against HepG2 cells, which induced G2/M phase arrest and apoptosis in HepG2 cells. HepG2 cells treated with LFEE (0.3 mg/mL) enhanced expressions of p53, tBid, Bad and Bax, along with decreased expressions of Bcl-2 and Bcl-xL, and induced the release of cytochrome c from mitochondria to cytosol. That also accompanied by activation of caspases-3, -8 and -9 and cleavage of poly (adenosine diphosphate (ADP)-ribose) polymerase (PARP); furthermore, down-regulations of phosphoinositide 3 kinase (PI3K), Akt, Akt phosphorylation and Bad phosphorylation could also be observed. Five flavonoids (total amount, 101.07 mg/g dried extract (g DE)), nine phenolic acids (total amount, 55.07 mg/ g DE) and proanthocyanidin A2 (81.20 mg/ g DE) could be determined in LFEE. [ABSTRACT FROM AUTHOR]

In our previous studies on 1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole (YC-1) analogs, we synthesised numerous substituted carbazole and α-carboline derivatives, which exhibited anticancer activity. In this study, we designed and synthesised a series of 3,9-substituted β-carbolines, by replacing the tricyclic rings of carbazole and α-carboline derivatives with isosteric β-carboline, and evaluated anticancer activity. We observed that 9-(2-methoxybenzyl)-β-carboline-3-carboxylic acid ( 11a ) inhibited the growth of HL-60 cells by inducing apoptosis, with a half maximal inhibitory concentration of 4.0 μM. Our findings indicate that β-carboline derivatives can be used as lead compounds for developing novel antitumor agents. [ABSTRACT FROM AUTHOR]

Background/Purpose The decoy receptor 3 (DcR3) is a member of the tumor necrosis factor receptor (TNFR) super-family. It counteracts the biological effects of Fas ligands and inhibits apoptosis. The goals of this study were to understand the associations between serologic DcR3 (sDcR3) levels and different human immunodeficiency virus type 1 (HIV-1) subtypes, as well as the AIDS disease progression. Methods Serum samples from 61 HIV/AIDS patients, who had been followed up every 6 months for 3 years, were collected. sDcR3 levels were quantified using an enzyme immunoassay (EIA). Results The sDcR3 levels in patients with HIV-1 subtype B were significantly higher than those in patients infected with subtype CRF01_AE ( p < 0.001). In addition, multivariable linear mixed model analysis demonstrated that HIV-1 subtype B and slow disease progression were associated with higher levels of sDcR3, adjusting for potential predictors ( p = 0.0008 and 0.0455, respectively). Conclusion HIV-1-infected cells may gain a survival advantage by activating DcR3, which prevents infected cell detection by the host immune system. These data indicate that the sDcR3 level is a biomarker for AIDS disease progression. [ABSTRACT FROM AUTHOR]

Justicidin A (JA), a novel arylnaphthalide lignan, was previously found to reduce the growth of human hepatocellular carcinoma cells (HCC), Hep 3B cells, in NOD-SCID mice via induction of apoptosis. Here, using L1000 microarray profiling obtained from JA-treated HCC cells, the z-score signatures of JA exhibited positive connectivity to known autophagy inducers among 3122 compounds from the Library of Integrated Network-based Cellular Signatures database. JA-induced autophagy in HCC Hep 3B cells was confirmed by formation of acidic vesicular organelles and an increase in the expression of LC3-II and LAMP2a. JA-induced autophagic flux was demonstrated by accumulation of LC3-II and LAMP2a, as well as a decrease in colocalization of LC3 and LAMP2a puncta in the presence of autophagy inhibitor bafilomycin A1. Administration of bafilomycin A1 also demonstrated that JA-induced autophagy suppressed apoptosis. Activation of Ras/MEK/ERK pathway was observed. Following administration of apoptosis inhibitor zVAD, it was found that JA-induced apoptosis did not affect JA-induced autophagy. It is noteworthy that addition of JA promoted chemosensitivity of sorafenib, the only FDA-approved targeted therapy for advanced HCC. The results demonstrate the effectiveness of this novel strategy for rapid discovery of molecular actions of small molecules and suggest the applications of JA in HCC treatment. [ABSTRACT FROM AUTHOR]

Previous studies have shown beneficial effects of mesenchymal stem cells (MSCs) transplantation in many autoimmune diseases. However, few studies have focused on the effects of MSCs on autoimmune hepatitis. In our study, we investigated the therapeutic effects of BMSCs (bone mesenchymal stem cells) transplantation in mouse experimental autoimmune hepatitis (EAH) and explored the potential mechanism. BMSCs were injected intravenously into EAH mice. Then, serum levels of ALT and AST, and pathologic alteration of liver tissue were measured to evaluate the liver function and inflammation degree. The expressions of programmed death ligand 1, IL-17 and IL-23 were detected by enzyme-linked immunosorbent assay (ELISA), reverse transcription-polymerase chain reaction (RT-PCR), and western blotting. Upon serum biochemical levels and pathological examination, the BMSCs-treated mice especially with multiple dosing administration showed significantly reduction of liver damage. Moreover, the expression of IL-17 was down-regulated by BMSCs intervention as compared to the model group, whereas the PD-L1 and IL-23 were up-regulated following the administration of MSCs. In conclusion, the results of this study suggest that BMSCs transplantation, especially on multiple dosing, may exert immunosuppression effect to ameliorate EAH through the inhibition of IL-17 and up-regulation of PD-L1. [ABSTRACT FROM AUTHOR]

Polygonatum odoratum lectin (POL), a mannose-binding GNA-related lectin, has been reported to display remarkable anti-proliferative and apoptosis-inducing activities toward a variety of cancer cells; however, the precise molecular mechanisms by which POL induces cancer cell death are still elusive. In the current study, we found that POL could induce both apoptosis and autophagy in human MCF-7 breast cancer cells. Subsequently, we found that POL induced MCF-7 cell apoptosis via the mitochondrial pathway. Additionally, we also found that POL induces MCF-7 cell apoptosis via EGFR-mediated Ras-Raf-MEK-ERK pathway, suggesting that POL may be a potential EGFR inhibitor. Finally, we used proteomics analyses for exploring more possible POL-induced pathways with EGFR, Ras, Raf, MEK and ERK, some of which were consistent with our in silico network prediction. Taken together, these results demonstrate that POL induces MCF-7 cell apoptosis and autophagy via targeting EGFR-mediated Ras-Raf-MEK-ERK signaling pathway, which would provide a new clue for exploiting POL as a potential anti-neoplastic drug for future cancer therapy. [ABSTRACT FROM AUTHOR]

Background/Purpose: Mechanical loading plays an important role in regulating bone formation and remodeling. Relevant mechanical stretching can increase the proliferation and differentiation of osteoblastic cells in vitro. However, little is known about the effects of supraphysiological high-level mechanical stretching on the growth and cell cycle progression of osteoblastic cells. Methods: Osteoblast-like MG-63 cells were seeded onto flexible-bottomed plates and subjected to cyclic mechanical stretching (15% elongation, 0.5 Hz) for 24 and 48 hours in a Flexercell FX-4000 strain unit. Cellular activities were measured by an assay based on the reduction of the tetrazolium salt, 3-[4,5-dimethyldiazol-2-yl]-2,5-diphenyl tetra-zolium bromide (MTT). The number of viable cells was also determined by the trypan blue dye exclusion technique. Cell cycle progression was checked by flow cytometry. mRNA expressions of apoptosis- and cell cycle-related genes (Bcl2, Bax, cdc2, cdc25C, and cyclin B1) were analyzed using an RT-PCR technique. Results: The number of viable cells significantly decreased in osteoblast-like MG-63 cells subjected to cyclic mechanical stretching for 24 or 48 hours. The MTT activity of stretched cells did not change at 24 hours, whereas a significant decrease was noted at 48 hours in comparison to the unstretched controls. The flow cytometry showed that mechanical stretching induced S-phase cell cycle arrest. Furthermore, exposure to mechanical stretching led to apoptotic cell death, as shown by the increase in the hypodiploid sub-G0/G1 cell population. Furthermore, a decreased cdc25C mRNA level was consistently noted in stretched cells. However, the mRNA expressions of Bcl2, Bax, cdc2, and cyclin B1 genes were not significantly altered compared to the unstretched control cells. Conclusion: High-level mechanical stretching induced S-phase cell cycle arrest and apoptotic cell death in osteoblastic cells. The results suggest that heavy tensional force is a negative regulator of osteoblastic activities and should, therefore, be minimized if bone formation is attempted during orthodontic/orthopedic treatment. [ABSTRACT FROM AUTHOR]

Abstract: Three heterocyclic hypervalent organoantimony chlorides RN(CH2C6H4)2SbCl (2a R = t-Bu, 2b R = Cy, 2c R = Ph) and their chalcogenide derivatives [RN(CH2C6H4)2Sb]2O (3a R = t-Bu, 3b R = Cy, 3c R = Ph) were synthesized and characterized by techniques such as 1H NMR, 13C NMR, X-ray diffraction, and elemental analysis. It is found that the anti-proliferative activity detected over these compounds can be attributed to the coordination bond between the antimony and nitrogen atoms of these compounds. Moreover, a preliminary study on mechanistic action suggests that the inhibition effect is ascribable to cell cycle arrest and cell apoptosis. [Copyright &y& Elsevier]

Abstract: To increase the efficacy of currently used anti-cancer genotoxins, one of the current efforts is to find agents that can sensitize cancer cells to genotoxins so that the efficacious doses of genotoxins can be lowered to reduce deleterious side-effects. In this study, we reported that a synthetic RasGAP-derived peptide GAP159 could enhance the effect of chemotherapeutic agent cisplatin (CDDP) in human colon carcinoma HCT116 cells. Our results showed that GAP159 significantly increased the CDDP-induced cytotoxicity and apoptosis in HCT116 cells. This synergistic effect was associated with the inhibitions of phospho-AKT, phospho-ERK and NF-κB. In mouse colon tumor CT26 animal models, GAP159 combined with CDDP significantly suppressed CT26 tumor growth, and GAP159 alone showed slight inhibitory effect. Our data suggests that co-treatment of GAP159 and chemotherapeutics will become a potential therapeutic strategy for colon cancers. [Copyright &y& Elsevier]

Abstract: Novel 6,7-methylenedioxy-4-substituted phenylquinolin-2(1H)-one derivatives 12a–n were designed and prepared through an intramolecular cyclization reaction and evaluated for in vitro anticancer activity. Among the synthesized compounds, 6,7-methylenedioxy-4-(2,4-dimethoxyphenyl)quinolin-2(1H)-one (12e) displayed potent cytotoxicity against several different tumor cell lines at a sub-micromolar level. Furthermore, results of fluorescence-activated cell sorting (FACS) analysis suggested that 12e induced cell cycle arrest in the G2/M phase accompanied by apoptosis in HL-60 and H460 cells. This action was confirmed by Hoechst staining and caspase-3 activation. Due to their easy synthesis and remarkable biological activities, 4-phenylquinolin-2(1H)-one analogs (4-PQs) are promising new anticancer leads based on the quinoline scaffold. Accordingly, compound 12e was identified as a new lead compound that merits further optimization and development as an anticancer candidate. [Copyright &y& Elsevier]

Abstract: Kaempferol is a polyphenol antioxidant found in fruits and vegetables. Many studies have described the beneficial effects of dietary kaempferol in reducing the risk of chronic diseases, especially cancer. Epidemiological studies have shown an inverse relationship between kaempferol intake and cancer. Kaempferol may help by augmenting the body’s antioxidant defence against free radicals, which promote the development of cancer. At the molecular level, kaempferol has been reported to modulate a number of key elements in cellular signal transduction pathways linked to apoptosis, angiogenesis, inflammation, and metastasis. Significantly, kaempferol inhibits cancer cell growth and angiogenesis and induces cancer cell apoptosis, but on the other hand, kaempferol appears to preserve normal cell viability, in some cases exerting a protective effect. The aim of this review is to synthesize information concerning the extraction of kaempferol, as well as to provide insights into the molecular basis of its potential chemo-preventative activities, with an emphasis on its ability to control intracellular signaling cascades that regulate the aforementioned processes. Chemoprevention using nanotechnology to improve the bioavailability of kaempferol is also discussed. [Copyright &y& Elsevier]

Abstract: Inflammation and hepatic stellate cell (HSC) activation are the most crucial steps in the formation of hepatic fibrosis. Hepatocytes damaged by viral or bacterial infection, alcohol or toxic chemicals initiate an inflammatory response that activates collagen production by HSCs. Recent studies indicate curcumin has liver-protective effects due to its anti-inflammatory, antioxidant and anticancer activities; however, the mechanisms are not well understood. In this study, we show that curcumin protected against hepatic fibrosis in BALB/c mice in vivo by inhibiting HSC activation, inflammatory responses and inducing apoptosis of damaged hepatocytes. Using the thioacetamide (TAA)-induced hepatic fibrosis animal model, we found that curcumin treatment up-regulated P53 protein expression and Bax messenger RNA (mRNA) expression and down-regulated Bcl-2 mRNA expression. Together, these responses increased hepatocyte sensitivity to TAA-induced cytotoxicity and forced the damaged cells to undergo apoptosis. Enhancing the tendency of damaged hepatocytes to undergo apoptosis may be the protective mechanism whereby curcumin suppresses inflammatory responses and hepatic fibrogenesis. These results provide a novel insight into the cause of hepatic fibrosis and the cytoprotective effects curcumin has on hepatic fibrosis suppression. [Copyright &y& Elsevier]

Abstract: Due to its malignancy, the development of effective therapeutic strategies for hepatocellular carcinoma (HCC) is of urgent needs. Natural antimicrobial peptides (AMPs), also known as host defense peptides (HDPs), not only act as direct antimicrobial agents, but also represent important regulators of the innate immune system. It has been reported that cationic AMPs may exhibit cancer-selective toxicity. We have designed a series of novel AMPs with potent antimicrobial activity against a broad spectrum of bacterial pathogens. In the current study, we evaluate the antitumor potency of these AMPs toward HCC cell lines J5, Huh7, and Hep3B. Selected AMPs inhibit the viability of HCC cells in a dose-dependent fashion, while the normal 3T3 cells were significantly less susceptible to these AMPs. GW-H1 treatment (20μM) of J5 cells for 24–72h resulted in the induction of apoptosis, as revealed by flow cytometry (increased sub-G1 populations), and western blot analysis for the appearance of activated caspase-3, -7 and -9 cleavages. Two-dimensional gel electrophoresis was applied to further analyze the AMP-responsive protein profiles of HCC, down-regulation of Hsp27, phophoglycerate kinase 1 and triosephosphate isomerase indicated that GW-H1 may induce apoptosis, and further inhibit progression and metastasis of J5 HCC cells. FITC-labeled GW-H1 was found to attach to cell membrane initially, then translocated into the cytoplasm, and eventually membranous organelles or nucleus. GW-H1 induced a marked growth suppression of J5 xenografts in nude mice in a dose dependent manner. These findings provided support for future application of GW-H1 as potential therapeutic agent for HCC. [Copyright &y& Elsevier]

Abstract: Protein phosphorylation plays a crucial role in the signal transduction pathways that regulate gene expression, metabolism, cell adhesion, and cell survival in response to oxidative stress. In this study, we have used hydrogen peroxide treatment of H9C2 rat cardiomyocytes as a model of oxidative stress in heart ischemia–reperfusion injury. We show that oxidative stress induces a robust tyrosine phosphorylation of multiple proteins in this cell type. A phosphoproteomics approach using anti-phosphotyrosine affinity purification and LC–MS/MS was then used to identify the protein targets of this stress-induced phosphorylation. Twenty-three tyrosine-phosphorylated proteins were identified, with the majority known to be associated with cell–cell junctions, the actin cytoskeleton, and cell adhesion. This suggested that oxidative stress may have a profound effect on intercellular connections and the cytoskeleton to affect cell adhesion, morphology, and survival. Importantly, Src kinase was shown to be a major upstream regulator of these events. Immunofluorescence studies, fluorescence-activated cell sorting, and cell-based assays were used to demonstrate oxidative stress-induced modification of cell adhesion structures and the cytoskeleton, induced de-adhesion, and increased apoptosis, which were reversed by treatment with the Src kinase inhibitor PP1. These data demonstrate the critical role of Src kinase in oxidative stress-induced phosphorylation and cell damage in cardiomyocytes and suggest that targeting this kinase may be an effective strategy for preventing ischemia–reperfusion injury in the heart. [Copyright &y& Elsevier]

Abstract: To compare the cytotoxicity of three nano-dentin bonding agents (nano-DBAs) and two non-nano-DBAs using Chinese hamster ovary (CHO-K1) cells. We found that nano fillers were not the major contributing factor in DBA cytotoxicity, as analyzed by colony forming assay and 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Exposure of CHO-K1 cells to all three tested total-etching DBAs led to G0/G1 cell cycle arrest, whereas exposure to higher concentrations of two tested nano-DBAs induced G2/M arrest. All five DBAs further induced apoptosis at the highest concentration, as analyzed by propidium iodide staining flow cytometry. The toxicity of all DBAs (1:4000v/v or higher) is related to increased reactive oxygen species (ROS) production, as analyzed by single cell DCF fluorescence flow cytometry. These results indicate that clinical application of DBAs may be potentially toxic to dental pulp tissues. Cytotoxicity of DBAs is associated with ROS production, cell cycle deregulation and apoptosis. Presence of methacrylate monomers such as PENTA and UDMA is possibly the major cytotoxic factor for DBAs. Further studies on other toxicological endpoints of nano-DBAs are necessary to highlight their safe use. [Copyright &y& Elsevier]

Abstract: The involvement of the central nervous system (CNS) or neuropsychosis has been reported in patients with systemic lupus erythematosus (SLE) and considered a major cause of long-standing functional impairment and mortality. However, little is known in the improvement of the brain abnormality in SLE. To investigate the effect and mechanism of cystamine on brain in SLE, NZB/W F1 mice were used as the animal model. Gel zymography, caspase-3 activity assay and Western blots were performed to elucidate the effect of cystamine. Significant reduction of matrix metalloproteinases (MMP)-9/MMP-2 ratio and urokinase-type plasminogen activator (uPA) expression was detected in brain of NZB/W F1 mice treated with cystamine as compared to control group. Significant increase of heat-shock protein (HSP)-70 and HSP27 was detected in brain of NZB/W F1 mice treated with cystamine as compared to control group. Additionally, significant reduction of mitochondrial dependent apoptosis was observed in brain of NZB/W F1 mice treated with cystamine as compared to control group by increasing BCL-2 and reducing caspase-9, Bad, and Apaf-1 expression. Moreover, increased phosphorylated p65 (NF-κB) protein was observed in brain of NZB/W F1 mice treated with cystamine as compared to control group. These experimental results firstly demonstrated the beneficial effects of cystamine on brain in NZB/W F1 mice and suggested the therapeutic potential in patients with neuropsychiatric SLE (NP-SLE). [Copyright &y& Elsevier]

Abstract: Hypoxia-induced retinal ganglion cell (RGC) death has been implicated in glaucomatous optic neuropathy. However, the precise mechanism of death signaling and how neuroprotective agents affect it are still unclear. The aim of this study is to characterize the mechanisms of hypoxia-induced apoptosis of cultured purified RGCs and to study the neuroprotective effects of beta-adrenergic antagonists. Rat RGCs were purified utilizing a modified two-step immuno-panning procedure. First, the extent of apoptosis in RGCs under hypoxia was quantified. Next, the effects of glutamate-channel antagonists (MK801 or DNQX), Bax inhibiting peptide (BIP), and beta-adrenergic antagonists (betaxolol, nipradilol, timolol or carteolol) on hypoxia-induced RGC death were investigated by the cell viability assay. Third, the effects of beta-adrenergic antagonists on hypoxia-induced increase of intracellular calcium concentrations ([Ca2+]i) and the additional effect of NO scavenger to nipradilol were evaluated. Apoptotic RGC percentages under hypoxia were significantly increased compared to the control. The viability of RGCs under hypoxia was not affected by MK801 or DNQX, whereas it was increased in a dose-dependent manner with exposure to BIP, and to betaxolol, nipradilol, timolol, but not to carteolol. These effective beta-adrenergic antagonists showed no significant change in hypoxia-induced [Ca2+]i levels. The NO scavenger alleviated neuroprotective effect by nipradilol. In conclusion, purified RGC damage induced by hypoxia involves Bax-dependent apoptotic pathway, but mostly independent of glutamate receptor-mediated excitotoxicity. Betaxolol, timolol and nipradilol showed a protective effect against hypoxia-induced RGC death, which was thought to be irrelevant either to calcium channel or β-adrenoceptor blocking effects. [Copyright &y& Elsevier]

Abstract: We previously demonstrated that the crude acetone extract of Bupleurum scorzonerifolium (BS-AE) 60μg/ml has anti-proliferation activity and apoptotic effects on A549 non-small cell lung cancer (NSCLC). A novel lignan, isochaihulactone (4-benzo[1,3]dioxol-5-ylmethyl-3(3,4,5-trimethoxyl-benzylidene)-dihydro-furan-2-one), was isolated from BS-AE and identified from spectral evidence (1H NMR, 13C NMR, IR, and MS) and by comparison with authentic synthetic standards. Isochaihulactone was cytotoxic (IC50 =10–50μM) in a variety of human tumor cell lines. In in vitro and in vivo microtubule assembly assays, it inhibited tubulin polymerization in a concentration-dependent manner. As determined by flow cytometry, isochaihulactone caused G2/M phase arrest and apoptosis in a time- and concentration-dependent manner. G2/M arrest was correlated with increased p21/WAF1 levels, downregulation of the checkpoint proteins cyclin B1/cdc2 and mobility shift of cdc25C. Moreover, isochaihulactone (30 and 50mg/kg) inhibited the growth of non-small cell lung carcinoma A549 xenograft in nude mice. These findings indicate isochaihulactone is a promising new antimitotic anticancer compound with potential for clinical application in the future. [Copyright &y& Elsevier]

Abstract: We previously demonstrated that the crude acetone extract of Bupleurum scorzonerifolium (AE-BS) 60 μg/ml has anti-proliferation activity and apoptosis effects to A549 human lung cancer cells. They can also cause tumor cell arrest in G2/M phase. To better understand its target protein in A549 cell, two-dimensional electrophoresis and liquid chromatography-tandem mass spectrometry were applied. The modification of keratin 8 was identified. By immunoblot, the expression of phosphorylated keratin 8 at Ser-73 was increased from 2.0 to 3.0-fold after AE-BS treatment 24 to 48 hr respectively as compared with untreated A549 control cells. Furthermore, the A549 cells were pretreated with 50 μM PD98059, a specific inhibitor of the upstream regulator of ERK1/2, or with the p38 kinase inhibitor 20 μM SB203580 or JNK inhibitor 20 μM SP600125 for 30 min, followed by 24 h of incubation with AE-BS, PD98059 can inhibit K8-Ser-73 hyperphosphorylation and prevented cell apoptosis which was induced by AE-BS significantly. By immunoblot, AE-BS also can induce ERK 1/2 phosphorylation. In conclusion, our data indicate that the AE-BS induced tumor apoptosis in A549 cells was related to ERK 1/2 activation. The molecular mechanism of hyperphosphorylation of K8 on Ser-73 was associated with ERK 1/2 activation rather than JNK and p38 kinase. The apoptosis induced by AE-BS may be related to K8 phosphorylation. [Copyright &y& Elsevier]

Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) is a type II acute-phase protein; however, the role of pulmonary ITIH4 after exposure to air pollution remains unclear. In this study, we investigated the role of ITIH4 in the lungs in response to air pollution. ITIH4 expression in bronchoalveolar lavage fluid (BAL) of 47 healthy human subjects and of Sprague-Dawley rats whole-body exposed to air pollution was determined, and the underlying antiapoptotic and matrix-stabilizing pathways in alveolar epithelial A549 cells induced by diesel exhaust particles (DEPs) as well as ITIH4-knockdown were investigated. We found that an interquartile range (IQR) increase in PM 2.5 was associated with a decrease of 2.673 ng/mL in ITIH4, an increase of 1.104 pg/mL of 8-isoprostane, and an increase of 6.918 pg/mL of interleukin (IL)-6 in human BAL. In rats, increases in 8-isoprostane, IL-6, and p53 and a decrease in sirtuin-1 (Sirt1) in the lungs and decreases in ITIH4 in the BAL, lungs, and serum were observed after PM 2.5 and gaseous exposure. ITIH4 levels in lung lysates were correlated with levels in BAL samples (r = 0.377, p < 0.01), whereas ITIH4 levels in BAL were correlated with IL-6 levels (r = −0.420, p < 0.01). ITIH4 expression was significantly reduced in alveolar epithelial A549 cells by DEP in a dose-dependent manner. A decrease in Sirt1 and increases in phosphorylated extracellular signal-regulated kinase (p-ERK) and caspase-3 were observed after DEP exposure and ITIH4-knockdown. In conclusion, air pollution decreased ITIH4 expression in the lungs, which was associated with alveolar epithelial cell senescence and apoptosis. ITIH4 could be a vital protein in regulating alveolar cell destruction and its inhibition after exposure to air pollution. [Display omitted] • PM 2.5 was associated with an ITIH4 deficiency in the lungs. • Decrease of ITIH4 by PM 2.5 presented in alveolar epithelial cells of rats. • Loss of ITIH4 activated apoptosis and senescence in alveolar epithelial cells. • ITIH4 may be a specific protein in response to PM 2.5 in alveolar epithelium. Capsule of main finding : The significance and novelty of this study are that ITIH4 regulates alveolar cell destruction by air pollution and thus could be an indicator of lung injury due to air pollution. [ABSTRACT FROM AUTHOR]

HKUST-1 is currently studied for a very diverse range of applications. Despite its exciting potential, significant concerns remain regarding the safety of HKUST-1. Therefore, human embryonic kidney 293 (HEK293) cells were used to verify the renal toxicity of HKUST-1. In this study, HKUST-1 induced concentration-dependent cytotoxic effects in HEK293 cells. The depolarization of mitochondrial membrane potential and formation of apoptotic bodies and autophagic vesicles were observed in HKUST-1–treated HEK293 cells. Oxidative (oxidative stress and haem oxygenase-1 activation) and inflammatory responses (NF-κB and NLRP3 activation) in HEK293 cells were induced by HKUST-1 exposure. In addition, the observed reduction in NAD(P)H levels in HKUST-1–treated HEK293 cells may be attributable to PARP-1 activation following DNA single- and double-strand breaks. The HKUST-1–induced depletion of zonula occludens proteins in HEK293 cells might lead to altered renal barrier integrity. The variations of α1-antitrypsin, oxidised α1-antitrypsin and NLRP3 protein expression in HEK293 cells suggested that HKUST-1 increases the risk of chronic kidney diseases. However, most of these adverse effects were significantly induced only by high HKUST-1 concentration (100 μg/mL), which do not reflect the actual exposure. Thus, the toxic risk of HKUST-1 appears to be negligible. Image 1 • HKUST-1 induces apoptosis and autophagy in HEK293 cells. • HKUST-1 decreases intracellular NAD(P)H due to DNA strand breaks in HEK293 cells. • HKUST-1 is associated with impaired renal barrier by depleting ZO proteins. • HKUST-1 increases the risk for chronic kidney disease. • Almost all of these adverse responses were induced by high level of HKUST-1. [ABSTRACT FROM AUTHOR]

Doxorubicin (Dox) is a potent anticancer agent, but its associated organ toxicity, including nephrotoxicity, restricts clinical applications. Dapagliflozin (DAPA), a sodium–glucose cotransporter-2 inhibitor, has been shown to slow the progression of kidney disease in patients with and without diabetes. However, the effect of DAPA to counteract Dox-induced nephrotoxicity remains uncertain. Therefore, in this study, we aimed to elucidate the effects of DAPA in mitigating Dox-induced nephrotoxicity. We analyzed the Taiwan National Health Insurance Database to evaluate the incidence of renal failure among breast cancer patients receiving Dox treatment compared to those without. After adjusting for age and comorbidities, we found that the risk of renal failure was significantly higher in Dox-treated patients (incidence rate ratio, 2.45; confidence interval, 1.41–4.26; p = 0.0014). In a parallel study, we orally administered DAPA to Sprague–Dawley rats for 6 weeks, followed by Dox for 4 weeks. DAPA ameliorated Dox-induced glomerular atrophy, renal fibrosis, and dysfunction. Furthermore, DAPA effectively suppressed Dox-induced apoptosis and reactive oxygen species production. On a cellular level, DAPA in HK-2 cells mitigated Dox-mediated suppression of the endothelial NOS pathway and reduced Dox-induced activities of reactive oxygen species and apoptosis-associated proteins. DAPA improved Dox-induced apoptosis and renal dysfunction, suggesting its potential utility in preventing nephrotoxicity in patients with cancer undergoing Dox treatment. • Cancer patients receiving Doxorubicin (Dox) had a higher risk of renal failure. • Dapagliflozin (DAPA) improved Dox-induced renal fibrosis, and dysfunction in rats. • DAPA mitigated Dox-activated reactive oxygen species in a cell model. • DAPA could be useful in preventing nephrotoxicity in cancer patients receiving Dox. [ABSTRACT FROM AUTHOR]

The Akt/glycogen synthase kinase-3β (GSK-3β)/β-catenin signaling pathway has been shown to play an important role in hematopoiesis, and hematopoietic cells are sensitive targets for benzene-induced hematotoxicity. We therefore hypothesized that dysregulation of the Akt/GSK-3β/β-catenin signaling was associated with benzene-induced hematotoxicity. Here, we showed that hydroquinone (HQ), a major metabolite of benzene in humans, significantly inhibited cell viability and colony formation while inducing apoptosis of human bone marrow mononuclear cells in vitro. Interestingly, we found that HQ inhibited the Akt affected β-catenin signaling by activation of GSK-3β, resulting in downregulation of β-catenin and its targets Cyclin D1 and Survivin. HQ blocked nuclear translocation of β-catenin and lymphoid enhancer-binding factor 1 (LEF-1), and importantly, HQ also reduced the interaction of β-catenin and LEF-1 in the nucleus. As expected, blockage of GSK-3β activity with a GSK-3β inhibitor lithium chloride (LiCl) or activation of Akt signaling with an Akt agonist insulin-like growth factor-1 (IGF-1) could inhibit HQ-induced activation of GSK-3β as well as hematotoxicity. Taken together, our results suggest that HQ-induced hematotoxicity in bone marrow mononuclear cells is associated with dysregulation of Akt/GSK-3β/β-catenin signaling due to the dissociation of β-catenin/LEF-1 complex, and LiCl and IGF-1 may be two potential agents to ameliorate HQ-induced hematotoxicity. [ABSTRACT FROM AUTHOR]

Objective: To determine whether a tumor necrosis factor-α (TNF-α) inhibitor can reduce the embryotoxicity of the peritoneal fluid (PF) of women with endometriosis. Design: Experimental clinical study. Setting: University hospital. Patient(s): Twelve women with chocolate cysts and 12 control women without endometriosis. Intervention(s): None. Main Outcome Measure(s): We collected the PF from patients with chocolate cysts (CH-PF) and patients without endometriosis (N-PF) during laparoscopic surgery. For the in vitro studies, development and apoptosis were evaluated in two-cell stage mouse embryos after incubation with CH-PF and N-PF, with or without a TNF-α inhibitor. Result(s): We found that CH-PF significantly decreased the rate of blastocyst development and increased the percentage of apoptotic cells in the embryos. Cytokine assays showed that the concentrations of several cytokines, including TNF-α, were higher in embryos incubated with CH-PF than in those incubated with N-PF. Furthermore, the treatment of embryos with TNF-α retarded development and induced apoptosis. Important, adalimumab, a TNF-α inhibitor, effectively abrogated the embryotoxicity that was induced by CH-PF. Conclusion(s): These data collectively highlight the crucial role of TNF-α in CH-PF-induced embryotoxicity and suggest that TNF-α inhibitors may be potential therapeutic agents for treating endometriosis-induced infertility. [ABSTRACT FROM AUTHOR]

Objective: To investigate if stem or progenitor cells are found in adenomyosis and to characterize the role of cyclooxygenase-2 (COX-2) in adenomyosis-derived mesenchymal stem cell (AMSC)–related pathogenesis of adenomyosis. Design: Experimental clinical study. Setting: University hospital. Patient(s): Ten patients with adenomyosis. Intervention(s): Hysterectomy. Main Outcome Measure(s): The gene expression of AMSCs and endometrial mesenchymal stem cells (EMSCs) were analyzed by microarray, quantitative polymerase chain reaction and Western blot. Methylthiazol tetrazolium, proliferation, apoptosis, and migration/invasion assays of AMSCs and EMSCs were evaluated after COX-2 inhibitor treatment. Result(s): We isolated nine EMSCs from normal endometrium (n = 10) and six AMSCs (n = 10) from adenomyosis. The morphology, phenotype, and potential of multilineage differentiation between EMSCs and AMSCs were not significantly different. Using complementary DNA microarrays, the expression profiles of EMSCs are related to those of bone marrow–derived mesenchymal stem cells (BMSCs), but AMSCs are different from EMSCs and BMSCs in the gene profiles. We validated the microarray results and showed that there is increased COX-2 expression in AMSCs compared with EMSCs. Treatment with a COX-2 inhibitor suppressed migration and invasion and induced apoptotic capabilities of AMSCs, but not of EMSCs. Conclusion(s): Overexpression of COX-2 in AMSCs may play an important role in the pathogenesis of adenomyosis. COX-2 could be a possible target for treatment and prevention of adenomyosis. [ABSTRACT FROM AUTHOR]

Lysosomal cell death is induced by lysosomal membrane permeabilization (LMP) and the subsequent release of lysosomal proteolytic enzymes, including cathepsins (CTSs), which results in mitochondrial dysfunction and apoptosis. Imiquimod (IMQ), a synthetic TLR7 ligand, has both antiviral and antitumor activity against various skin malignancies in clinical treatment. Previously, we demonstrated IMQ not only caused lysosomal dysfunction but also triggered lysosome biogenesis to achieve lysosomal adaptation in cancer cells. To determine whether lysosomes are involved in IMQ-induced apoptosis. The human skin cancer cell lines BCC, A375 and mouse melanoma cell line B16F10 were used in all experiments. Cell death was determined by the Cell Counting Kit-8 (CCK-8) assay and DNA content assay. Protein expression was determined by immunoblotting. Caspase-8 activity was assessed using a fluorescence caspase-8 kit and determined by flow cytometry and confocal microscopy. IMQ not only induced lysosome damage but also abrogated lysosome function in skin cancer cells. IMQ-induced caspase-8 activation contributed to the processes of lysosomal cell death. Moreover, the use of ROS scavengers significantly abolished caspase-8 activation and inhibited IMQ-induced LMP. Additionally, pharmacological inhibition of CTSD not only abrogated caspase-8 activation but also rescued IMQ-induced cell death. Finally, lysosome-alkalizing agents enhanced the cytotoxicity of IMQ in vitro and in vivo. IMQ-induced ROS accumulation promotes LMP, releases CTSs into the cytosol, stimulates caspase-8 activation and finally causes lysosomal cell death. Lysosomal cell death and the CTSD/caspase-8 axis may play a crucial role in IMQ-induced cell death. • IMQ causes lysosomal membrane permeabilization and CTSs releasing into cytosol in skin cancer cells. • IMQ induces lysosomal cell death which is mediated by CTSD/caspase-8 axis. • IMQ-induced ROS generation is crucial for IMQ-induced caspase-8 activation and lysosomal cell death. • Combination treatment with lysosome-alkalinizing agents and IMQ enhances anti-tumor response in skin cancer cells. [ABSTRACT FROM AUTHOR]

In this paper, a series of cyclometalated bismuth(III) complexes bearing C,O -bidentate ligands were synthesized and characterized by techniques such as UV–vis, NMR, HRMS, and single crystal X-ray diffraction. Meanwhile, their cytotoxicities against various human cell lines, including colon cancer cells (HCT-116), breast cancer cells (MDA-MB-231), lung cancer cells (A549), gastric cancer cells (SGC-7901), and normal embryonic kidney cells (HEK-293) were assessed in vitro. Compared with the clinical cisplatin, most of the synthesized complexes possessed significantly higher degrees of anticancer activity and selectivity, giving a selectivity index of up to 71.3. The structure-activity relationship study revealed that the anticancer performance of these bismuth(III) species depends on the factors of coordination environment surrounding the metal center, such as coordination number, coordination bonding strength, lone 6s2 electron pair stereoactivity. The Annexin V-FITC/PI double staining assay results suggested that the coordination environment-dependent cytotoxicity is ascribable to apoptosis. Western blot analysis confirmed the proposal, as evidenced by the down-regulating level of Bcl-2 and the activation of caspase-3. Furthermore, the representative complexes Bi1 , Bi4 , Bi6 , and Bi8 exhibited relatively lower inhibitory efficiency on human ovarian cancer cells (A2780) than on its cisplatin-resistant daughter cells (A2780/cis), thus demonstrating that such compounds are capable of circumventing the cisplatin-induced resistance. This investigation elucidated the excellent anticancer performance of C,O -coordinated bismuth(III) complexes and established the correlation between cytotoxic activity and coordination chemistry, which provides a practical basis for in-depth designing and developing bismuth-based chemotherapeutics. The relationship between coordination environment and anticancer activity of cyclometalated bismuth(III) complexes with C,O -chelating ligands against various human solid tumor cell lines was elucidated. [Display omitted] • Nine C,O -coordinated bismuth(III) complexes were synthesized as anticancer agents. • The cytotoxicity depended on the coordination environment surrounding the metal center. • Most of the synthesized complexes exhibited high tumor cell selectivity. • The coordination number-environment cytotoxicity was ascribable to cell apoptosis. • These bimuth(III) complexes could circumvent the cisplatin-induced resistance. [ABSTRACT FROM AUTHOR]

[Display omitted] • Regulated cell death (RCD) refers to apoptosis, autophagy-dependent cell death, necroptosis, and other subroutines. • Apoptosis, autophagy-dependent cell death and necroptosis have many links to carcinogenesis. • Small-molecule compounds modulate some RCD pathways that are key for cancer therapy. • Targeting of RCD subroutines is a potential strategy for cancer drug discovery. Evasion of regulated cell death (RCD), mainly referring to apoptosis, autophagy-dependent cell death, necroptosis, and other subroutines, is one of the well-established hallmarks of cancer cells. Accumulating evidence has revealed several small-molecule compounds that target different subroutines of RCD in cancer therapy. In this review, we summarize key pathways of apoptosis, autophagy-dependent cell death and necroptosis in cancer, and describe small-molecule compounds that target these pathways and have potential as therapeutics. These inspiring findings light the way towards the discovery of more 'magic bullets' that could work individually or cooperatively to target precisely the three RCD subroutines and so improve cancer treatment. [ABSTRACT FROM AUTHOR]

Programmed cell death (PCD) is a genetically regulated process of cell suicide essential for plant development. The 'malate valve' is a mechanism that ensures redox balance across different subcellular compartments. In broccoli, the BomMDH1 gene encodes malate dehydrogenase in mitochondria, a critical enzyme in the 'malate circulation' pathway. This study investigates the functional role of BomMDH1 in malate (MA)-induced apoptosis in bright yellow-2 (BY-2) suspension cells. Findings revealed that transgenic cells overexpressing BomMDH1 showed enhanced viability under MA-induced oxidative stress compared to wild-type (WT) cells. Overexpression of BomMDH1 also reduced levels of reactive oxygen species (ROS), hydrogen peroxide (H 2 O 2), and malondialdehyde (MDA), while increasing the expression of antioxidant enzyme genes such as NtAPX , NtAOX1a , NtSOD , and NtMDHAR. Additionally, treatment with salicylhydroxamic acid (SHAM), a characteristic inhibitor of mitochondrial respiration, further improved the anti-apoptotic activity of BY-2 cells. Overall, these results highlighted the function of the BomMDH1 gene and the potential of SHAM treatment in mitigating oxidative stress in BY-2 suspension cells. • Malate treatment accelerated the yellowing process of broccoli. • Overexpressing BomMDH1 in BY-2 cells exhibited stronger cell viability. • Confirmed the effective role of SHAM in BY-2 suspension cells exposed to MA. [ABSTRACT FROM AUTHOR]

Plant senescence is the final period of the plant life cycle and represents a programmed cell death (PCD) process. Melatonin, a versatile signaling molecule, exhibits potent free radical scavenging properties and actively participates in cellular antioxidant systems, effectively retarding plant senescence throughout its development. In order to illustrate the impact of melatonin on PCD during senescence, we examined the effects of exogenous melatonin at 80 μmol L−1 on PCD and mitochondrial function in broccoli bud cells at 25 ℃. The findings revealed that melatonin treatment not only maintained the morphological integrity of chloroplasts and mitochondria but also attenuated the decline in chlorophyll content by reducing the expression of genes that metabolize chlorophyll, including BoPPH , BoPAO , and BoSGR1. In comparison to the control group, the treatment decreased the content of H 2 O 2 and the rate of O 2 - production in mitochondria and simultaneously enhanced the activities of ascorbate peroxidase (APX), catalase (CAT), and superoxide dismutase (SOD), resulting in effective maintenance of reactive oxygen species (ROS) homeostasis and reduction of the level of lipid peroxidation in broccoli buds during senescence. Meanwhile, exogenous melatonin treatment up-regulated alternative oxidase (AOX) activity and its gene expression while delayed the reduction of cytochrome oxidase (COX) activity and restrained the over-opening of mitochondrial permeability transition pores (MPTP). Additionally, exogenous melatonin decelerated the increase in membrane potential and prevented mitochondria from releasing excess cytochrome c (Cyt c) into the cytoplasm. Taken together, the results indicate that melatonin treatment delayed mitochondrial dysfunction, preserved mitochondrial ROS homeostasis, and consequently postponed the initiation of PCD, ultimately inhibiting senescence in broccoli. ● Exogenous melatonin protects the structural of chloroplasts and mitochondrial. ● Exogenous melatonin down-regulates the chlorophyll degrading gene. ● Exogenous melatonin reduces mitochondrial dysfunction in broccoli. ● Exogenous melatonin delays the decline of APX, CAT and SOD activities. ● Exogenous melatonin delays the occurrence of programmed cell death in broccoli. [ABSTRACT FROM AUTHOR]

It is well established that programmed cell death (PCD) occurred in broccoli during postharvest senescence, but no studies have been conducted on the regulation of broccoli cytochrome f by mannose treatment and its relationship with PCD. In this study, we treated broccoli buds with mannose to investigate the changes in color, total chlorophyll content, gene expression related to chlorophyll metabolism, chloroplast structure, and cytochrome f determination during postharvest storage. In addition, to investigate the effect of cytochrome f on PCD, we extracted cytochrome f from broccoli and treated Nicotiana tabacum L. cv Bright Yellow 2 (BY-2) cells with extracted cytochrome f from broccoli at various concentrations. The results showed that cytochrome f can induce PCD in tobacco BY-2 cells, as evidenced by altered cell morphology, nuclear chromatin disintegration, DNA degradation, decreased cell viability, and increased caspase-3-like protease production. Taken together, our study indicated that mannose could effectively delay senescence of postharvest broccoli by inhibiting the expression of gene encoding cytochrome f which could induce PCD. • Mannose treatment delayed the senescence process of broccoli. • Mannose maintained chloroplast structure and mitigated degradation in broccoli. • Cytochrome f from broccoli induced PCD in BY-2 cells. [ABSTRACT FROM AUTHOR]

Phosphatidylinositol 3-kinase (PI3K) δ-specific inhibitors have been approved for the therapy of certain types of B cell lymphoma (BCL). However, their clinical use is limited by the substantial toxicity and lack of efficacy in other types of BCL. Emerging evidence indicates that PI3Kα plays important roles in the progression of B cell lymphoma. In this study, we revealed that PI3Kα was important for the PI3K signaling and proliferation in BCL cells. A novel clinical PI3Kα-selective inhibitor CYH33 possessed superior activity against BCL compared to the marketed PI3Kα-selective inhibitor Alpelisib and PI3Kδ-selective inhibitor Idelalisib. Though CYH33 was able to inhibit PI3K/AKT signaling in tested BCL cells, differential activity against proliferation was observed. Transcriptome profiling revealed that CYH33 down-regulated "MYC-targets" gene set in sensitive but not resistant cells. CYH33 inhibited c-MYC transcription in sensitive cells, which was attributed to a decrease in acetylated H3 bound to the promoter and super-enhancer region of c-MYC. Accordingly, CYH33 treatment resulted in phosphorylation and proteasomal degradation of the histone acetyltransferase p300. An unbiased screening with drugs approved or in clinical trials for the therapy of BCL identified that the clinical BET (Bromodomain and Extra Terminal domain) inhibitor OTX015 significantly potentiated the activity of CYH33 against BCL in vitro and in vivo, which was associated with enhanced inhibition on c-MYC expression and induction of cell cycle arrest and apoptosis. Our findings provide the rationale of combined CYH33 with BET inhibitors for the therapy of B cell lymphoma. [ABSTRACT FROM AUTHOR]

Abstract: Compounds 4a–f, 5a–f and 6–9, showed significant growth inhibition activity against human tumor cell lines. Of these compounds, 1-(2-((Z)-6-(2-(trifluoromethyl)phenyl)hexa-3-en-1,5-diynyl)phenyl)piperidin-2-one (8) displayed the most potent growth inhibition activity. Compound 8 also arrested cancer cells in G2/M phase and induced apoptosis via activation of caspase-3 and -9. According to western-blotting analysis, compound 8 can up-regulate Bax, down-regulate Bcl-2 and XIAP, as well as promote cytochrome c release. [Copyright &y& Elsevier]

Traffic emission is responsible for most small-sized particulate matter (PM) air pollution in urban areas. Several recent studies have indicated that traffic-related PM may aggravate kidney disease. Furthermore, exposure to particulate air pollution may be related to the risk of chronic kidney disease (CKD). However, the underlying molecular mechanisms have not been adequately addressed. In the present study, we studied the mechanisms of renal damage that might be associated with exposure to PM. In a real world of whole-body exposure to traffic-related PM model for 3–6 months, PM in urban ambient air can affect kidney function and induce autophagy, endoplasmic reticulum (ER) stress and apoptosis in kidney tissues. Exposure to traffic-related diesel particulate matter (DPM) led to a reduction in cell viability in human kidney tubular epithelial cells HK-2. DPM increased mitochondrial reactive oxygen species (ROS) and decreased the mitochondrial membrane potential. Furthermore, DPM induced ER stress and activated the unfolded protein response (UPR) pathway. Eventually, DPM exposure induced caspase pathways and triggered apoptosis. In addition, DPM induced autophagy through the inhibition of the Akt/mTOR pathway. Autophagy inhibition resulted in significantly increased cytotoxicity and apoptosis. These findings suggest that air pollution in urban areas may cause nephrotoxicity and autophagy as a protective role in PM-induced cytotoxicity. Image 1 • PM affected kidney function in a whole-body exposure to traffic-related PM model. • DPM induced ER stress and the activation of the UPR pathway in kidney cells. • DPM caused mitochondrial damage by increasing ROS and reducing membrane potential. • DPM induced autophagy by inhibiting the Akt/mTOR pathway. [ABSTRACT FROM AUTHOR]

Bushen-Yizhi formula (BSYZ), a traditional Chinese medicine (TCM) prescription widely used in treating mental retardation and neurodegenerative diseases with kidney deficiency, has been reported to attenuate oxidative stress-related neuronal apoptosis. Chronic cerebral hypoperfusion (CCH) is considered to be related to cognitive and emotional disorders. However, it remains to be clarified that the effect of BSYZ on CCH and its underlying mechanism. In the present study, we aimed to investigate the therapeutic effects and underlying mechanisms of BSYZ on CCH- injured rats based on the domination of oxidative stress balance and mitochondrial homeostasis through inhibiting abnormal excessive mitophagy. The in vivo rat model of CCH was established by bilateral common carotid artery occlusion (BCCAo), while the in vitro PC12 cell model was exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) condition, and a mitophagy inhibitor (chloroquine) by decreasing autophagosome-lysosome fusion was used as reverse validation in vitro. The protective role of BSYZ on CCH-injured rats was measured by open field test, morris water maze test, analysis of amyloid fibrils and apoptosis, and oxidative stress kit. The expression of mitochondria-related and mitophagy-related proteins was evaluated by Western blot, immunofluorescence, JC-1 staining assay and Mito-Tracker Red CMXRos assay. The components of BSYZ extracts were identified by HPLC-MS. The molecular docking studies were used to investigate the potential interactions of characteristic compounds in BSYZ with lysosomal membrane protein 1 (LAMP1). Our result indicated that BSYZ improved the cognition and memory abilities of the BCCAo rats by diminishing the occurrence of apoptosis and abnormal amyloid deposition accumulation, suppressing oxidative stress damage for abnormal excessive mitophagy activation in the hippocampus. Moreover, in OGD/R-damaged PC12 cells, BSYZ drug serum treatment substantially enhanced the PC12 cell viability and suppressed intracellular reactive oxygen species (ROS) accumulation for protecting against oxidative stress, along with the improvement of mitochondrial membrane activity and lysosomal proteins. Our studies also showed that inhibiting of autophagosome-lysosome fusion to generate autolysosomes by using chloroquine abrogated the neuroprotective effects of BSYZ on PC12 cells regarding the modulation of antioxidant defence and mitochondrial membrane activity. Furthermore, the molecular docking studies supported the direct bindings between lysosomal associated membrane protein 1 (LAMP1) and compounds in BSYZ extract to inhibit excessive mitophagy. Our study demonstrated that BSYZ played a neuroprotective role in rats with CCH and reduced neuronal oxidative stress via promoting the formation of autolysosomes to inhibit abnormal excessive mitophagy. [Display omitted] [ABSTRACT FROM AUTHOR]

Ovarian cancer is one of the leading causes of death related to the female reproductive system in western countries. Adverse side effects and resistance to platinum based chemotherapy have become the major obstacles for ovarian cancer treatment. Natural products have gained great attention in cancer treatment in recent years. Chinese bayberry leaves flavonoids (BLF) containing rich content of myricitrin (myricetin 3- O -rhamnoside) and a part of quercetrin (quercetin 3-rhamnoside) inhibited the growth of an ovarian cancer cell line A2780/CP70. Such inhibitory effects might be due to the induction of apoptosis and G1 cell cycle arrest. BLF treatment increased the expression of cleaved caspase-3 and -7 and induced apoptosis via a Erk-dependent caspase-9 activation intrinsic apoptotic pathway by up-regulating the pro-apoptotic proteins (Bad and Bax) and down-regulating the anti-apoptotic proteins (Bcl-xL and Bcl-2), which were also in consistency with the results from Hoechst 33342 staining and flow cytometry analysis. Furthermore, by reducing the expression of cyclin D1 and CDK4 and p-Erk, BLF elevated the distribution of G1 phase in cell cycle and thus caused G1 cell cycle arrest. Overall, these results indicated that BLPs could be a valuable resource of natural compound for ovarian cancer treatment. [ABSTRACT FROM AUTHOR]

Eukaryotic elongation factor 2 kinase (eEF2K) is a Ca 2+ /calmudulin-dependent protein kinase, belonging to a small family of an atypical Ser/Thr-protein kinase. eEF2K has been recently reported to be highly activated or overexpressed in many types of cancer; therefore, eEF2K would be regarded as a promising therapeutic target. In this study, we discovered a β-phenylalanine scaffold by virtual high-throughput screening, as well as designed and synthesized 46 derivatives with assessment of inhibition activity against eEF2K and cytotoxicity. After several rounds of kinase and anti-proliferative activity screening, we discovered an eEF2K inhibitor ( 21l ) with best eEF2K enzymatic activity (IC 50 of 5.5 μM) and anti-proliferative activity (MDA-MB-231 cells, IC 50 of 12.6 μM, MDA-MB-436 cells, IC 50 of 19.8 μM). Moreover, we found that 21l could induce cell death via the apoptotic pathways in MDA-MB-231 and MDA-MB-436 cells. Subsequently, we evaluated its anti-tumor activity and apoptosis-inducing mechanisms in vivo . These results suggested that 21l inhibited tumor growth by apoptosis in the xenograft mouse model of breast cancer (MDA-MB-231 and MDA-MB-436). Collectively, our results demonstrate a novel small-molecule inhibitor targeting eEF2K with mechanism of apoptosis and a therapeutic potential in breast cancer. [ABSTRACT FROM AUTHOR]